TSPO Ligands for Cancer Imaging

描述（由申请人提供）：该多学科提案旨在开发和验证一类用于快速临床部署的新型癌症成像生物标志物。利用基础和临床癌症生物学、创新药物化学和高通量小分子筛选方面的进展，我们的实验室已经确定了肿瘤选择性转运蛋白（TSPO）配体，这些配体是进一步开发作为正电子发射断层扫描（PET）显像剂的有希望的候选者。TSPO是一种18 kDa的高亲和力胆固醇和药物结合蛋白，参与胆固醇代谢、类固醇生物合成、增殖和凋亡。肿瘤中TSPO水平升高已被充分证实，其水平与肿瘤的增殖、侵袭和转移有关。此外，我们的实验室已经将胶质瘤中TSPO配体结合与丝裂原活化蛋白激酶（MAPK）信号传导机制联系起来。利用这一观察结果，我们已经证明TSPO配体PET可以用于评估这种情况下MAPK通路的抑制作用。总的来说，这些数据证明了TSPO配体PET作为肿瘤学预测成像生物标志物的潜在意义。本研究的总体目标是开发临床可翻译的、肿瘤选择性的TSPO成像配体，以促进人类胶质瘤的检测、分子表征和预后。我们的具体目标是[1]优化新的肿瘤选择性TSPO配体先导物用于体内PET成像，[2]开发用正电子发射同位素氟-18标记有前途的TSPO配体的方法，[3]评估有前途的TSPO成像配体。

DESCRIPTION (provided by applicant): This multidisciplinary proposal seeks to develop and validate a novel class of cancer imaging biomarkers for rapid clinical deployment. Leveraging advances in basic and clinical cancer biology, innovative medicinal chemistry, and high-throughput, small molecule screening, our laboratory has identified tumor-selective translocator protein (TSPO) ligands that are promising candidates for further development as positron emission tomography (PET) imaging agents. TSPO is an 18 kDa high-affinity cholesterol- and drug-binding protein that participates in cholesterol metabolism, steroid biosynthesis, proliferation, and apoptosis. Elevated levels of TSPO are well-documented in oncology, where levels correlate with tumor proliferation, invasion, and metastasis. Furthermore, our laboratory has mechanistically linked TSPO ligand binding to mitogen-activated protein kinase (MAPK) signaling in glioma. Capitalizing upon this observation, we have shown that TSPO ligand PET can be used to evaluate MAPK pathway inhibition in this setting. Collectively, these data demonstrate the potential significance of TSPO ligand PET as a predictive imaging biomarker in oncology. The overall goal of this study is to develop clinically translatable, tumor-selective TSPO imaging ligands that facilitate improved detection, molecular characterization, and prognosis of human gliomas. Our Specific Aims are [1] to optimize novel, tumor-selective TSPO ligand leads for in vivo PET imaging, [2] to develop methods for labeling promising TSPO ligands with the positron-emitting isotope fluorine-18, and [3] to evaluate promising TSPO imaging ligands in vivo.